Pain is the predominant means by which illness and physical dysfunction are detected in humans and animals. Most diseases involve pain as a symptom, and the absence of pain often signifies the lack of a pathology.
Pain is increasingly seen as having a physical component and a psychological component. Thus, pain may involve a physical sensation, caused by certain stimuli of certain nerves and the subsequent transmission of pain impulses to the central nervous system. Alternatively, or concurrently, pain may involve a stressful state of mind linked to emotion, depression, or anguish. Thus, recently some have begun to regard pain, particularly certain types of pain such as chronic pain (including phantom, allodynia and/or neuropathic pain), as having certain elements in common with psychiatric or neurophysiological and neurodegenerative disorders.
According to current pain theory, the physical sensation of pain is mediated by two types of afferent nerve fibers in the distal axons of primary sensory neurons. These fibers respond maximally to nociceptive (i.e. potentially tissue-damaging) stimuli. One fiber is a very fine, unmyelinated, slowly conducting fiber (the C fiber), and the other is a thinly myelinated, more rapidly conducting fiber termed the A-delta (A-δ) fiber. The peripheral terminals of these primary pain afferents are highly branched nerve endings in the skin and other organs. There are three broad categories (with possible subcategories) of free nerve endings: mechanoreceptors (those that respond to innocuous mechanical stimulation); thermoreceptors (those that respond to innocuous heat stimulation); and polymodal nociceptors (these respond best to noxious stimuli, but can transmit impulses in response to thermal, chemical or mechanical stimuli. Additionally, certain A-delta fibers can respond to light touch, temperature and pressure as well as to pain, and seem to do so in proportion to the level of stimulus.
The peripheral afferent pain fibers have their cell bodies in the dorsal root ganglia. Central extensions of these neurons project to the dorsal horn of the spinal cord, where they terminate. Fast-conducting secondary ascending afferent neurons transmit the pain impulses to nuclei in the thalamus, medulla, pons and midbrain.
Additionally, groups of slowly conducting fibers project, for example, to the reticular core of the medulla and midbrain and then to the medial and intralaminar nuclei of the thalamus. One such group of fibers is called the spinoreticulothalamic pathway. In the medulla, these fibers synapse in the nucleus gigantocellularis.
These slow-conducting fiber systems appear to conduct diffuse, poorly localized pain from deep and visceral structures in the body, and it has been proposed that they are involved in the unpleasant feelings caused by pain, including the psychic aspects of pain, even when the direct, fast-moving pathways have been interrupted. However, neural projections from the ventral posterolateral thalamus project directly to the sensory cortex to mediate the sensory-discriminative aspects of pain, such as location, quality, and perhaps intensity. The pathways for visceral pain from the esophagus, stomach and bowels are carried largely by the vagus nerve and terminate in the nucleus of the solitary tract (NST) before projecting to the thalamus; other abdominal viscera appear to reach the NTS by other pathways, as they still activate the NTS when the vagus nerve is severed.
In addition to the ascending pain pathways from the sensory neurons to the brain, there are also descending pain-related pathways. One such pathway originates in the brain (the frontal cortex and hypothalamus) and projects to the midbrain, pons, medulla and spinal cord. Other descending pathways (e.g., noradrenergic and serotoninergic) originate in the locus coeruleus, dorsal raphe nucleus and nucleus reticularis gigantocellularis and appear to modulate the nociceptive response.
As indicated above, acute nociceptive pain is a reaction to tissue-injuring stimuli, such as pricking, cutting, crushing, burning and freezing. However, these stimuli do not result in pain in all tissues; pain receptors are activated by different stimuli, depending on the tissue. So, for example, in the stomach and intestine pain is produced by stimuli such as inflamed mucosa and distension or spasm of the smooth muscle. In skeletal muscle pain is caused by eschemias, necrosis, hemorrhage, injection of irritating solutions, and prolonged contraction. Distension of arteries (as occurs in thrombolyic and embolic occlusion) can cause pain, as can excessive arterial pulsation. The latter may be a cause (or as has been more recently suggested, a symptom) of migraine pain. Other mechanisms of headache may be neurogenic in nature.
When tissue is damaged there is liberation of proteases from injured cells. These proteases act locally on tissue proteins to directly or indirectly liberate substances that stimulate pain receptors. Some of these substances include histamine, prostaglandins, serotonin and potassium ions. Also, the receptors themselves cause the liberation of pain-enhancing substances such as Substance P, which is released from the nerve endings of C fibers in the skin during peripheral nerve stimulation. Substance P causes erythema and edema and recruits leukocytes in a reaction called neurogenic inflammation.
The threshold of pain perception for a given stimulus is approximately the same for all humans. This pain threshold is reduced by inflammation and in a condition termed allodynia, tissue becomes sensitized such that ordinarily innocuous stimuli, such as light touching or brushing, becomes painful. The pain threshold is increased through administration of anesthetics or analgesics.
The human body comprises a neuronal analgesia system, which can be activated by substances including opiates and naturally occurring brain chemicals, such as the endorphins, having pharmacologic properties of opiates. Stimulation of various loci within the brain results in the suppression of nociceptive responses and are relayed to the dorsal horn gray matter via a pathway in the spinal cord.
Opiates act pre- and post-synaptically in neurons of the A-delta and C fibers, suppressing afferent pain impulses. The endorphins appear to act through an endogenous system stimulated most strongly by prolonged pain and fear; for example, some soldiers wounded in battle appear to require little or no analgesic medication, probably due to activation of this latter system. This phenomenon is known as stress-induced analgesia. As an example of one way in which this system operates, the endorphin enkephalin binds the opiate receptors at the point of entry of pain fibers into the spinal cord and inhibits the release of the chemical transmitter Substance P. Thus, the post-synaptic neuron receives less stimulation by Substance P, and therefore transmits less excitatory pain impulses to the brain.
Descending pain-control systems other than the opiate system have been identified; noradrenergic and serotoninergic pain pathways have been described in mammals, although their precise mechanism has not yet been described. Activation of a norepinephrinergic pathway from the pons to the spinal cord blocks spinal nociceptive receptors, while descending serotoninergic fibers from the medulla inhibit dorsal horn cells concerned with pain transmission.
“Hyperalgesia” is a term that refers to an increased sensitivity to painful stimulus, while “hypoalgesia” connotates the opposite. An increased reaction to a painful stimulus once it is perceived is termed “hyperpathia”, which results in the symptom of allodynia. Allodynic pain has unusual features which are modifiable by fatigue, emotion, etc., and is a common feature of neuropathic or neurogenic pain such as pain resulting from peripheral neuropathy. For example, “causalgia” is a specific type of burning pain resulting from interruption of a peripheral nerve.
“Deep pain” from visceral and skeletomuscular structures tends to be aching in quality, and sharp when intense. It is diffuse and poorly localized. “Referred pain” is pain, such as deep pain, which is projected to (felt to occur in) some fixed site at some distance from the source.
In recent years there has begun to be recognition that there is a difference between acute pain (usually associated with the nociceptive receptors and involving potential or actual tissue damage) and the phenomenon of chronic pain. By “chronic pain” is meant to include, without limitation, neuropathic pain, referred pain, phantom pain, allodynia, visceral pain, deep pain, and the like resulting from myriad conditions including, without limitation, arthritis, headache (including tension and migraine headache), musculoskeletal pain (such as back pain) cancer, and bowel disorders, such as irritable bowel syndrome (IBS).
One difference between chronic and acute pain mentioned above concerns the stress-related and psychic effects of chronic pain. Continuous pain increases irritability, fatigue, depression, disturbs sleep, impairs appetite, and can deprive the subject of psychic and physical strength.
Common classes of drugs used as analgesics broadly include opioids, nonopioid analgesics (such as non-steroid anti-inflammatory agents, or NSAIDs), anticonvulsants and tricyclic antidepressants. The effectiveness of each of these drug types for different types of pain indicates that pain is a complex phenomenon in which different mechanisms may be in play depending on the particular nature of the pain stimulus.
NSAIDs such as aspirin, ibuprofen and acetaminophen appear to function by inhibiting the synthesis of prostaglandins and therefore the prostaglandin-mediated activation of nociceptors. Opioids act as “false” neurotransmitters at the endorphin receptor sites in the posterior horns of the spinal cord. Opioids also exert a powerful action of the psychic “affective” component of pain.
Tricyclic antidepressants such as, doxepin, amitriptyline, Imipramine, nortriptyline and Desipramine are used as serotonin reuptake inhibitors (SRIs), thus enhancing the activity of serotonin at synapses and theoretically facilitating the endogenous opiate analgesic system. Some of the newer SRIs do not appear to be as effective as the older, less specific ones, at treating chronic neuropathic pain. Victor, M. & Ropper, Alan H., Principles of Neurology Ch. 8 153 (7th Ed. 1997).
Anticonvulsants, such as phenytoin, carbamazepine, clonazepam, and gabapentin, are useful in the treatment of some central and peripheral neuropathic pains, but seem to be less effective at treating causalgic pain. The mechanism of analgesic action of these agents is not understood.
In addition, alpha 2 adrenoreceptors have been long been known to be involved in analgesia, and compounds having alpha 2 agonist activity have been used clinically since 1984. See Kingery, W. S. et al., Molecular Mechanisms for the Analgesic Properties of Alpha-2 Adrenergic Agonists in Molecular Neurobiology of Pain 275 (IASP Press 1997). Such agents, for example, clonidine, tizanidine and dexmedetomidine—which are not subtype-selective alpha 2 agonists—have mainly been used in perioperative analgesia due to significant sedative and cardiovascular effects. Because of these effects, intrathecal administration has been the route of choice. Systemically administered alpha 2 agonists have been shown to have significant analgesic activity, but treatment has been limited by the lower threshold of sedative activity. Very low systemic doses of clonidine and dexmedetomidine cause sedation, bradycardia and hypotension; indeed, the ED50 of these drugs for sedation is significantly lower than the ED50 for analgesia.
Particularly with respect to neurological and chronic pain, there appear to be certain commonalities between the biochemistry of pain and that of neurological and neurodegenerative disease. For example, nerve injury, such as nerve crush or ligation, is often used as a model for both chronic pain and for neurodegenerative disorders such as glaucoma. Also, some neurological diseases, such as certain forms of Charcot-Marie-Tooth syndrome (a group of conditions affecting the function or structure of peripheral nerve axons or the lipid-containing myelin sheath encasing them) involve disorders of lipid metabolism or catabolism.
Neurodegeneration is a term which includes the apoptotic destruction of neuronal tissue as well as the degenerative disorders involving neuronal, myelin, or tissue breakdown, with degradation products liberated from damaged cells evoking even more tissue destruction and phagocytosis. Conditions involving apoptosis are usually gradual and not metabolically based; those involving the more traumatic degenerative processes often have a metabolic origin.
Many diseases involving neurodegeneration begin gradually after a long period of normal nervous system function and are progressive, usually over a period of years. Among such conditions, without limitation, are:                I. Syndromes of Progressive Dementia (e.g., Alzheimer's disease, diffuse cerebral cortical atrophy of non-Alzheimer's origin, Lewy body dementia, Pick disease, frontotemporal dementia, thalamic dementia, Huntington chorea, non-Huntington chorea, cortical-striatal-spinal degeneration (Jakob) and the dementia-Parkinson-amyotrophic lateral sclerosis complex, dentatorubropallidoluysian degeneration (DRPLA), cerebrocerebellar degeneration, familial dementia with spastic paraparesis, amyotrophy, or myoclonus, Lewy body disease, Parkinson disease (some cases), corticobasal ganglionic degeneration, polyglucosan body disease)        II. Syndrome of Disordered Posture and Movement (e.g., Parkinson's disease, Shy-Drager syndrome, multiple system atrophy, progressive supranuclear palsy, dystonia, Hallervorden-Spatz disease, corticobasal ganglionic degeneration, torticollis, Meige syndrome, familial tremors, Tourette syndrome, acanthocytic chorea)        III. Syndrome of Progressive Ataxia (e.g., Friedreich ataxia, non-Friedreich early onset ataxia, cerebellar cortical ataxias, olivopontocerebellar degenerations (OPCA), dentatorubral degeneration (Ramsey Hunt type), dentatorubropallidoluysian atrophy, Machado-Joseph, Azorean disease, other ataxias with retinopathy, pigmentary retinopathy, ophthalmoplegia, slow eye movements (Wadia), neuropathy, optic atrophy, deafness and dementia.)        IV. Syndrome of Slowly Developing Muscular Weakness or Atrophy (e.g., amyotrophic laterial sclerosis (ALS), progressive spinal muscular atrophy, progressive bulbar palsy, spastic paraplegia, primary lateral sclerosis)        V. Sensory and Sensorimotor Disorders (e.g., Charcot-Marie-Tooth syndrome, hypertrophic interstitial polyneuropathy, Refsum disease)        VI. Syndrome of Progressive Blindness e.g., Optic neuropathy, retinitis pigmentosa, Stargardt disease, diabetic retinopathy, macular degeneration, glaucoma, progressive external ophthalmoplegia with or without other system atrophies)        VII. Syndromes Characterized by Neurosensory Deafness (e.g., pure neurosensory deafness, hereditary hearing loss with retinal diseases, hereditary hearing loss with system atrophies of the nervous system.)        
At the molecular level, the possible causes of neurodegeneration are diverse. Glutamate and glycine-induced excitotoxicity and nitric oxide toxicity are all implicated as possible causes of neural cell death, although these very agents are released from already injured cells. Many neurodegenerative conditions are associated, either primarily or secondarily, with ischemia, although other conditions appear to involve ischemia, if at all, as a result of neural injury, rather than as a causal factor.
Furthermore, while not classified as a neurodegenerative disorder, Gaucher disease is, strictly speaking, a disorder of lipid storage, which may have neural sequelae. There are three types of Gaucher disease, and all are characterized by a genetic deficiency in the enzyme glucocerebrosidase, which is responsible for the recycling of the glycolipid glucocerebroside into the sugar glucose and the lipid ceramide. In affected individuals, macrophages lacking a functional glucocerebrosidase accumulate glucocerebroside in their lysozymes, and can be identified microscopically by their distended shape. These cells are characteristic of the disorder, and known as Gaucher cells. Gaucher cells gather in the spleen (causing spleen overactivity, anemia, and leukocytopenia), the liver (occasionally causing scarring of the liver), and bone marrow (where they may interfere with blood cell production and cause brittleness of the bone tissue). Gaucher cells can also be observed accumulating in neural tissue.
The iminosugar-like molecule N-butyl-1-deoxy-nojirimycin (NB-DNJ) is currently approved for use in Europe and the United States for the treatment of mild to moderate Gaucher disease under the trade name Zavesca®. NB-DNJ is an inhibitor of the glycolipid pathway enzyme ceramide specific glucosylceramide transferase. Inhibition of this enzyme prevents the accumulation of sphingolipids involved in the synthesis of glucocerebroside, and thus prevents the accumulation of this glycolipid in macrophages.
More recently, NB-DNJ has been shown to inhibit normal mammal spermatogenesis at concentrations less than those shown to be effective in the treatment of Gaucher disease; sperm cells have a high lipid content, and glycosphingolipids are involved in spermatogenesis. See, e.g., van der Spoel, Aarnoud C. et al., Proc. Natl. Acad. Sci. 99:17173 (Dec. 23, 2002).